The objective of the research is to elucidate the participation of certain metabolically significant chemicals in the mechanisms which mediate local regulation of blood flow. The literature suggests that the most likely chemical candidates for such a role are O2, K ion, H ion, and adenosine or its mononucleotides. Recent data suggests that some responses may be initiated by certain chemicals but maintained by others. Therefore, our studies will be directed at testing the hypothesis that 1) K ion acts to begin the dilation of active hyperemia in skeletal muscle, and 2) the response is maintained by an interaction of O2, H ion and ATP. At onset of exercise in skeletal muscle the venous effluent shows an increased K ion and plasma osmolality. While these changes are not found in steady state exercise, the pO2 and pH of this venous blood is reduced. Concurrent with these changes is an increase in plasma ATP. Since this blood produces dilation when perfused into other organs (compared to blood from resting skeletal muscle), it is suggested that the agent (s) imparting this dilatory property are also responsible for the vasodilation in exercising muscle. Therefore, we propose to correct these changes in venous blood from exercising muscle with a dialyzer and gas permeator. If these corrections alter the time course or magnitude of response in an assay organ, this will provide data relative to the mechanism which mediates this form of local regulation. We will also determine if acute decreases in oxygen and pH cause release of ATP from the blood or from various systemic organs. This type of information will allow us to speculate on the mechanism of the vascular response to hypoxia and hypercapnia. It is hoped that these studies may ultimately lead to a better understanding of the local mechanisms that operate within organs and vascular beds to, in part, control their blood supply.